The invention relates to benzoxa- and benzthiazole derivatives. It concerns a benzoxa- or benzthiazole substituted at the 2 position and carrying a sulfamic acid ester group bound via oxygen to the phenyl part of the ring structure, hereinafter briefly named xe2x80x9ca compound of the inventionxe2x80x9d.
More specifically, it concerns a compound of formula I 
wherein
X is O or S;
R1 and R2 either independently are hydrogen or alkyl, or one is hydrogen and the other is acyl or alkoxycarbonyl; and
R3 is alkyl; alkenyl; alkinyl; cycloalkyl; cycloalkenyl; aryl; acyl; cycloalkylalkyl; cycloalkylalkenyl, including cycloalkanylidenealkyl; cycloalkenylalkyl; arylalkyl; arylalkenyl; arylalkinyl; alkoxycarbonylaminoalkyl; hydroxycycloalkylalkyl; cycloalkanylidenecycloalkanylidenalkyl; heteroaryl; or heteroarylalkyl;
in free form or salt form.
The sulfamoyloxy moiety in formula I is bound to the ring system in position 5 or 6, preferably 6.
Alkyl as a group R1 or R2 preferably is of 1 to 4 carbon atoms, it especially is methyl. Acyl as a group R1 or R2 preferably is formyl or alkylcarbonyl of altogether 2 to 5 carbon atoms, it especially is acetyl. Alkoxycarbonyl as a group R1 or R2 preferably is of altogether 2 to 5 carbon atoms, it especially is methoxycarbonyl.
In significance R3:
akyl as such or as part of a substituent such as cycloalkylalkyl includes (C1-22)alkyl, e.g. (C1-16)alkyl and (C1-4)alkyl;
alkenyl as such or as part of a substituent such as cycloalkylalkenyl includes (C2-22)alkenyl, e.g. (C2-16)alkenyl and (C2-4)alkenyl; when it is part of cycloalkanylidenealkyl the double bond is attached directly to the cycloalkyl moiety and thus the alkenyl part of such a cycloalkylalkenyl group is to be viewed as consisting of just one carbon atom;
alkinyl as such or as part of a substituent such as arylalkinyl includes (C2-22)alkinyl;
cycloalkyl as such or as part of a substituent such as cycloalkylalkyl or hydroxycycloalkylalkyl includes (C4-12)cycloalkyl, such as cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclododecanyl; it may be mono- or polycyclic, such as bridged cycloalkyl, as in adamantyl, hexahydro-2,5-methanopentalenyl; bicyclo[3.3.1]nonyl, or it may be cycloalkyl annexed to a second ring system, e.g. a second cycloalkyl, such as decalin (octahydronaphthyl), and includes spiro cycloalkyl, as in 1,4-dioxo-spiro[4.5]decyl or 1,5-dioxo-spiro[5.5]undecyl, whereby the cycloalkyl moiety and the annexed second ring system are unsubstituted or substituted with e.g up to 4, preferably one or two alkyl or alkoxy moieties of preferably 1 or 2 carbon atoms; when cycloalkyl is part of a substituent, there preferably is just one, but there may be up to two, mono- or polycyclic cycloalkyl moieties, as in e.g. dicyclohexylmethyl;
cycloalkenyl as such or as part of cycloalkenylalkyl includes (C4-12)cycloalkenyl, such as cyclohexenyl; it may be polycyclic, as in e.g. decahydrophenanthrenyl, and may be substituted, e.g. with 1 to 3 (C1-4)alkyl;
aryl as such or as part of arylalkyl, arylalkenyl or arylalkinyl includes (C5-18)aryl, e.g. (C5-12)aryl, e.g. phenyl or tetrahydronaphthalinyl, and may be substituted by e.g. alkyl; there may be up to 3, preferably 1 aryl moiety when aryl is part of a substituent, as in di- or triphenylmethyl;
aryl includes the residue of a carboxylic acid, in particular an alkyl, aralkyl or aryl carboxylic acid, e.g. an alkyl, aralkyl or aryl carbocyclic acid;
cycloalkylalkenyl includes e.g. a cycloalkanylidenalkyl group of formula i 
wherein
R4 is hydrogen or alkyl, e.g. (C1-4)alkenyl, especially methyl, and
R5 and R6 together with the carbon atom to which they are attached form cycloalkyl;
cycloalkenylalkyl is e.g. cyclohexenylmethyl;
alkoxycarbonylaminoalkyl is e.g. tert-butoxycarbonylamino-2,2-dimethylpropyl;
in hydroxycycloalkylalkyl the hydroxy group preferably is bound to the cycloalkyl part at the same carbon atom that is bound to the alkylene part of the hydroxycycloalkylalkyl moiety;
cycloalkanylidenecycloalkanylidenalkyl is e.g. bicyclobutylidenylidenemethyl;
heteroaryl as such or as part of heteroarylalkyl preferably is pyridyl or thienyl.
X preferably is oxygen, R1 and R2 preferably are hydrogen. R3 preferably is alkyl; cycloalkylalkyl; cycloalkenylalkyl; alkoxycarbonylaminoalkyl; or cycloalkylalkenyl, e.g. a group of formula i as defined above.
A subgroup of compounds of the invention is the compounds of formula I wherein
X is as defined above;
R1 and R2 are hydrogen; and
R3 is alkyl, alkenyl, cycloalkyl or cycloalkenyl,
in free form or salt form.
A further subgroup of compounds of the invention is the compounds of formula Is 
wherein X, R4, R5 and R6 are as defined above; in free form or salt form.
A further subgroup of compounds of the invention is the compounds of formula It 
wherein X, R1, R2 and R4 are as defined above; in free form or salt form; e.g. sulfamic acid 2-(adamantan-2-ylidenemethyl)benzoxazol-6-yl ester in free form or salt form.
A further subgroup of compounds of the invention is the compounds of formula Ip1 
wherein
either R1p and R2p have the significances indicated above for R1 and R2; and
R3p1 is alkyl; alkenyl; alkinyl; cycloalkyl; acyl; cycloalkylalkyl; arylalkyl; arylalkenyl; arylalkinyl; heteroaryl; or heteroarylalkyl;
or R1p and R2p are hydrogen; and
R3p1 is adamantan-2-ylidenemethyl;
in free form or salt form.
A further subgroup is the compounds of formula Ip2 
wherein
R1 and R2 are as defined above; and
R3p2 is alkyl; alkenyl; alkinyl; cycloalkyl; acyl; cycloalkylalkyl; adamantylalkenyl, including adamantanylidenalkyl; arylalkyl; arylalkenyl; arylalkinyl; heteroaryl; or heteroarylalkyl;
in free form or salt form.
A further subgroup is the compounds of formula Iq 
wherein X is as defined above and
R3q is
(C1-13)alkyl;
(C10-16)alkenyl;
cycloalkyl selected from adamantyl and hexahydro-2-5-methano-pentalenyl;
the cycloalkenyl moiety 7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthren-1-yl;
an aryl moiety 5,6,7,8-tetrahydronaphthalenyl;
cycloalkyl selected from adamantylalkyl of 1 to 4 carbon atoms in the alkylene part thereof and dicyclohexylmethyl;
cycloalkylalkenyl (including cycloalkanylidenalkyl) selected from:
adamantanyliden(C1-4)alkyl; (C4-12)cycloalkylidene(C1-4)alkyl; bicyclo[3.3.1]nonylidenemethyl; dimethylcyclohexylidenemethyl; (C1-4)alkoxycyclohexylidenemethyl; (C1-4)alkylcyclohexylidenemethyl; tetra(C1-4)alkylcyclohexylidenemethyl; 1,4-dioxaspiro[4.5]dec-8-ylidenemethyl; 3,3-dimethyl-1,5-dioxo-spiro[5.5]undec-9-ylidenemethyl; and octahydronaphthalylidenemethyl;
cyclohexenyl(C1-4)alkyl;
arylalkyl selected from di- or triphenyl(C1-4)alkyl;
(C1-4)alkoxycarbonylamino(C1-6)alkyl;
hydroxycycloalkylalkyl selected from: (2-hydroxyadamant-2-yl)(C1-6)alkyl; (9-hydroxybicyclo[3.3.1]non-9-yl(C1-4)alkyl; and
1-hydroxy-2,2-dimethylcyclohexyl(C1-4)alkyl; or
a cycloalkanylidenecycloalkanylidenalkyl moiety bicyclobutylidenylidenemethyl;
in free form or salt form.
A compound of the invention includes a compound in any form, e.g. in free form, in the form of a salt, in the form of a solvate and in the form of a solvated salt.
A salt of a compound of the invention includes a pharmaceutically acceptable salt, e.g. an acid addition salt. A compound of the invention in free form may be converted into a corresponding compound in the form of a salt and vice versa. A compound of the invention in the form of a solvate in free form or salt form may be converted into a corresponding compound in free form or salt form in unsolvated form and vice versa.
A compound of the invention may exist in the form of isomers and mixtures thereof; e.g. a compound of the invention may contain substituents exhibiting geometric isomerism and/or asymmetrically substituted carbon atoms and may thus exist in the form of isomers and/or diastereoisomers and mixtures thereof. Isomeric mixtures may be separated in conventional manner to obtain pure isomers or diastereoismers, respectively, The invention includes a compound of the present invention in any isomeric and/or diasteroisomeric pure form and in the form of any isomeric and/or diastereoisomeric mixture.
The invention further includes a process for the preparation of a compound of the invention as defined above, comprising sulfamoylating a corresponding benzoxa- or benzthiazole substituted in the 2 position and carrying a hydroxy group on the phenyl part of the ring structure.
More specifically, it concerns a process for the preparation of a compound of formula I as defined above, in free form or salt form, comprising
a) when R1 and R2 are both hydrogen, sulfamoylating a compound a formula II 
xe2x80x83wherein X and R3 are as defined above, or
b) when one or of both R1 and R2 are other than hydrogen, appropriately N-substituting a compound of formula I wherein R1 and R2 are both hydrogen,
and recovering the resultant compound of formula I in free form or salt form.
The process of the invention may be effected in conventional manner.
Process variant a) may be carried out e.g. by reacting a compound of formula II
a1) with sulfuryl chloride and sodium- or potassium azide, and reducing the azide group to an amino group xe2x80x94NH2 in a resultant compound of formula III 
xe2x80x83wherein X and R3 are as defined above; or
a2) with Clxe2x80x94SO2xe2x80x94NCO and submitting the product obtained to aqueous hydrolysis; or
a3) with a compound of formula IV 
xe2x80x83wherein R1 and R2 are both hydrogen and L is a leaving group, e.g. halogen, preferably chloro; such as H2Nxe2x80x94SO2xe2x80x94Cl;
e.g. in an inert solvent, e.g. dimethylformamide or dimethylacetamide, with or without addition of an organic base, such as an organic tertiary amine, or an inorganic base, e.g. an alkali(hydrogen)carbonate or alkali hydride, preferably sodium hydride.
Process variant b) may be effected by N-alkylating, N-acylating or N-alkoxycarbonylating using e.g. for N-alkylation activated alkyl, e.g. alkyl halogenides, such as alkyl iodides, alkyl sulfates or alkyl mesy(tosy)lates; for N-acylation acyl halogenides; and for N-alkoxycarbonylation alkoxycarbonyl halides, preferably chlorides. The reaction is effected conveniently in the presence of a suitable base, preferably an alkali metal carbonate or alkali metal hydride, preferably in an inert, preferably polar solvent such as acetone or dimethylformamide, at temperatures between about xe2x88x9220xc2x0 and about +120xc2x0 C., preferably between room temperature and about 60xc2x0 C.
A resultant compound of the invention may be recovered from the reaction mixture and isolated and purified in conventional manner. Isomers, such as geometric isomers or enantiomers or diastereoisomers, may be obtained in conventional manner, e.g. by fractional crystallization or asymmetric synthesis from corresponding asymmetrically substituted, e.g. optically active starting materials.
The starting materials may also be prepared in conventional manner. A compound of formula II may e.g. be obtained by
xcex1) reacting a compound of formula V 
xe2x80x83wherein X is as defined above, with a compound of formula R3xe2x80x94COHal, wherein Hal is halogen, e.g. chloro, and R3 is as defined above and, if desired, further reacting a resultant compound of formula II with sulfuryl chloride and sodium- or potassium azide to obtain a compound of formula III; or
xcex2) for the production of a compound of formula IIa 
xe2x80x83wherein X, R4, R5 and R6 are as defined above, reacting a compound of formula IIb 
xe2x80x83wherein R4 and X are as defined above, with a compound of formula VI 
xe2x80x83wherein R3 and R6 are as defined above, e.g. in the presence of trimethylsilyl chloride (TMSCl), N-ethyldiisopropylamine and sodium bis(trimethylsilyl)amide in an inert solvent, e.g. tetrahydrofurane, at low temperatures, e.g. around xe2x88x9270xc2x0 C., and dehydrating a resultant compound of formula IIc 
xe2x80x83wherein X, R4, R5 and R6 are as defined above, e.g. by treatment with trifluoroacetic acid in an inert solvent such as toluene.
Process variant a3) above is also indicated for the preparation of a compound of formula I wherein R1 and R2 are hydrogen, X is as defined above and R3 is a group of formula i as defined above, starting from a corresponding compound of formula IIc and dehydrating a resultant compound of formula I wherein R3 is hydroxycycloalkylalkyl as described under xcex2) above.
Alternatively a compound of formula II may be obtained by reaction of a compound of formula V with a compound of formula R3COOH, conveniently in the presence of propylphosphonic acid anhydride and N-ethyl-diisopropylamine; or 2,2xe2x80x2-dithiopyridine and triphenylphosphane; preferably in an inert solvent, e.g. methylene chloride, and cyclizing a resultant compound of formula VII 
wherein X and R3 are as defined above, e.g. in the presence of diethylazodicarboxylate and triphenylphosphine in an inert solvent, e.g. tetrahydrofurane, at e.g. room temperature.
Alternatively a compound of formula IIa may be obtained by reaction of a compound of formula VIII 
wherein X and R4 are as defined above and Alk is alkyl, preferably methyl, with a compound of formula VI, e.g. in the presence of butyl lithium in an inert solvent, e.g. tetrahydrofurane, conveniently at low temperatures, such as around xe2x88x9270xc2x0 C.,
to obtain a compound of formula IX 
wherein Alk, X, R4, R5 and R6 are as defined above; and either
dealkylating to obtain a compound of formula IIc and then dehydrating, e.g. as described under xcex2) above, to obtain a corresponding compound of formula IIa; or
dehydrating first, e.g. as described under xcex2) above, to obtain a compound of formula X 
xe2x80x83wherein Alk, X, R4, R5 and R6 are as defined above; and then dealkyltaing to obtain a corresponding compound of formula IIa, e.g. in the presence of pyridine and HCl, conveniently at high temperatures, such as above about 100xc2x0 C., e.g. around 200xc2x0 C.
Many starting materials and intermediates are either known or can be prepared according to known methods or analogously as described in the Examples.
The compounds of formula IIa, IIc, IX and X in free form or salt form are novel and also form part of the invention.
The following Examples illustrate the invention. Temperatures are in degrees Celsius. NMR values are for 13C-NMR spectra at 62.9 MHz in CDCl3 unless indicated otherwise. The following abbreviations are used:
DMA=dimethylamide
DMSO=dimethylsulfoxide
Ex.=Example
m.p.=melting point